Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides

DOI: 10.1126/science.ade3332

Authors: Hannah Bridges (University of Cambridge) , James N. Blaza (University of Cambridge; The University of York) , Zhan Yin (University of Cambridge) , Injae Chung (University of Cambridge) , Michael N. Pollak (McGill University) , Judy Hirst (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 379 , PAGES 351 - 357

State: Published (Approved)
Published: January 2023
Diamond Proposal Number(s): 22238 , 17057

Abstract: The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo–electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.

Diamond Keywords: Diabetes; Type 2 Diabetes

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios III-Titan Krios III at Diamond , Krios IV-Titan Krios IV at Diamond

Added On: 01/02/2023 09:09

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)